Amantadine (Systemic)

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Antiviral (systemic)—

antidyskinetic—

antifatigue, specifically in multiple sclerosis—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.Accepted

Influenza A (prophylaxis and treatment)—Amantadine is indicated as a primary agent in the prophylaxis and treatment of respiratory tract infections caused by influenza A virus strains {41} in high-risk patients (including those with pulmonary or cardiovascular disease, the elderly, and residents of nursing homes and other long-term care facilities who have chronic medical conditions), hospital ward contacts of high-risk patients, immunocompromised patients, those in critical public service positions (e.g., police, firefighters, medical personnel), in high-risk patients for whom the influenza vaccine is contraindicated, and patients with severe influenza A viral infections. It is effective against all strains of influenza A virus that have been tested to date, including Russian, Brazilian, Texan, London, and others. It may be given as chemoprophylaxis concurrently with inactivated influenza A virus vaccine until protective antibodies develop. However, it should be emphasized that vaccination of high-risk persons each year is the single most important measure for reducing the impact of influenza. No well-controlled studies have examined whether amantadine prevents complications of influenza A in high-risk persons. {21}{30}{40}
—Resistant strains of influenza A have been reported in patients receiving rimantadine; these resistant strains were also apparently transmitted to household contacts. {35} Rimantadine has a similar chemical structure, spectrum of activity, and mechanism of action to amantadine {36}, and drug-resistant strains of virus have cross-resistance to amantadine and rimantadine. {35}

Extrapyramidal reactions, drug-induced (treatment) or
Parkinsonism (treatment)—Amantadine is indicated in the treatment of idiopathic parkinsonism (paralysis agitans; shaking palsy), postencephalitic parkinsonism, drug-induced extrapyramidal reactions, including parkinsonism syndrome, dystonia, and akathisia {44}, symptomatic parkinsonism following injury to the nervous system caused by carbon monoxide intoxication, and parkinsonism associated with cerebral arteriosclerosis in the elderly. {03}{41}
—Amantadine has been used alone or in combination with anticholinergic antiparkinson drugs and with levodopa to treat parkinsonism. The final therapeutic benefit seen with amantadine is significantly less than that seen with levodopa. {44}

[Fatigue, multiple sclerosis–associated(treatment)]1—Amantadine is used in the management of certain aspects of fatigue associated with multiple sclerosis, including lowered energy level, decreased sense of well-being, decreased perceived attention and memory, and diminished problem solving ability. {23}{24}{25}Unaccepted
Amantadine is not effective against other respiratory viral infections, including influenza B and parainfluenza. {03}

Amantadine is not effective in the management of drug-induced tardive dyskinesia. {44}

Antiviral (systemic)—Not completely understood; amantadine appears to block the uncoating of influenza A virus and the release of viral nucleic acid into respiratory epithelial cells. May also affect early replicative phase of viruses that have already penetrated cells. {26}

Antidyskinetic—Unknown; amantadine causes an increase in dopamine release in the animal brain. Probably increases release of dopamine and norepinephrine from central nerve terminals; also inhibits the reuptake of dopamine and norepinephrine. {27}{28}Absorption:

Rapidly and almost completely absorbed from gastrointestinal tract. {03}Distribution:

Approximately 0.3 mcg per mL; steady-state trough concentrations after 50, 200, and 300 mg per day are approximately 0.1, 0.3, and 0.6 mcg per mL, respectively. Plasma concentrations exceeding 1.0 mcg per mL are considered to be in the toxic range. {17}{18}{26}Elimination:
Renal; > 90% excreted unchanged in urine by glomerular filtration and renal tubular secretion. Rate of excretion rapidly increased in acid urine. {03}{12}{26}
In dialysis—Only small amounts (approximately 4%) removed from the blood by hemodialysis. {29}

Amantadine was negative for mutagenesis in the Ames test and in a mammalian cell line assay using Chinese hamster ovary cells, both with and without metabolic activation. No evidence of chromosomal damage was observed in either an in vitro test using lymphocyes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test at doses of 140 to 550 mg per kg of body weight (mg/kg) (estimated human equivalent doses of 11.7 to 45.8 mg per kg of body weight, based on body surface area conversion). {41}Pregnancy/Reproduction
Fertility—
Slightly impaired fertility was observed in a three-litter reproduction study performed in rats at a dose of 32 mg/kg per day (estimated human equivalent dose of 4.5 mg/kg per day, based on body surface area conversion). However, no effects on fertility were seen at a dose of 10 mg/kg per day (estimated human equivalent dose of 1.4 mg/kg per day, based on body surface area conversion). No tests were perfomed using intermediate doses. {41}

Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to and during the IVF cycle. {41}

Pregnancy—
Amantadine crosses the placenta. However, adequate and well-controlled studies in humans have not been done. Both tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant whose mother was exposed to 100 mg amantadine orally for 7 days during the sixth and seventh weeks of gestation. Cardiovascular maldevelopment (single ventricle with pulmonary atresia) has been associated with maternal exposure to 100 mg of amantadine daily administered during the first 2 weeks of pregnancy. Amantadine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. {41}

Studies in animals have shown that amantadine is embryotoxic and teratogenic in rats at doses of 50 mg/kg per day. No adverse effects were seen in rats at doses of 37 mg/kg per day. {03}{44} No embryotoxic or teratogenic effects were seen in rabbits that received 32 mg/kg per day (estimated human equivalent dose of 9.6 mg/kg per day, based on body surface area conversion). {41}

Amantadine is distributed into breast milk. {03} However, the effects of amantadine in neonates and infants are not known. Use is not recommended in nursing mothers. {41}{44}Pediatrics

Appropriate studies on the relationship of age to the effects of amantadine have not been performed in neonates and infants up to one year of age. However, use of amantadine in children older than l year of age has not been shown to cause any pediatrics-specific problems that would limit its usefulness in children. {03}{41}

Geriatrics

Geriatric patients may exhibit increased sensitivity to the anticholinergic-like side effects of amantadine, including confusion. A dosage reduction of 50% (£ 100 mg per day) appears to reduce the frequency of side effects without compromising antiviral prophylactic effectiveness. In addition, elderly patients are more likely to have an age-related decline in renal function, which may require a dosage reduction of greater than 50% in patients receiving amantadine, depending on the extent of renal dysfunction. {03}{40}

Dental

Prolonged use of amantadine may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol (concurrent use with amantadine is not recommended since this may increase the potential for central nervous system (CNS) effects such as dizziness, lightheadedness, orthostatic hypotension, or confusion)

» Anticholinergics (see Appendix II ), or other medications with anticholinergic activity, or
Antidepressants, tricyclic or
Antidyskinetics, other or
Antihistamines or
Phenothiazines (concurrent use with amantadine may potentiate the anticholinergic-like side effects, especially those of confusion, hallucinations, and nightmares; dosage adjustments of these medications or of amantadine may be necessary; also, patients should be advised to report the occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy)

Antidiarrheals, opioid- and anticholinergic-containing (concurrent use with amantadine may potentiate the anticholinergic-like side effects; although significant interaction is unlikely with usual doses of opioid- and anticholinergic-containing antidiarrheal agents, significant interaction may occur if these medications are abused)

Carbidopa and levodopa combination or
Levodopa (concurrent use with amantadine may result in increased efficacy of carbidopa and levodopa combination, and levodopa; however, concurrent use is not recommended if there is a history of psychosis {03})

» CNS stimulation–producing medications, other (see Appendix II ) (concurrent use with amantadine may result in additive CNS stimulation to excessive levels, which may cause unwanted effects such as nervousness, irritability, or insomnia, and possibly seizures or cardiac arrhythmias; close observation is recommended {03})

Hydrochlorothiazide and
Triamterene (one or both of these drugs may reduce the renal clearance of amantadine, resulting in increased plasma concentrations and possible amantadine toxicity {22})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Risk-benefit should be considered when the following medical problems exist
Eczematoid rash, recurrent, history of{41}» Edema, peripheral{41} or» Heart failure, congestive{41} (amantadine may cause congestive heart failure and peripheral edema; presumed to be due to redistribution of fluid, not a gain of body water {27})

» Epilepsy, history of, or other seizure disorders{41} (amantadine may cause increased seizure activity; it may be necessary to reduce the dosage by 50% [£ 100 mg per day]; this appears to reduce the frequency of side effects without compromising antiviral prophylactic effectiveness)

Hypersensitivity to amantadine{41}
Psychiatric disorders, history of or
Substance abuse, history of (amantadine can exacerbate mental problems in patients with a history of these conditions {41})

Psychosis or severe psychoneurosis{41} (anticholinergic-like side effects of amantadine may result in confusion, hallucinations, and nightmares; it may be necessary to reduce the dosage by 50% [£ 100 mg per day]; this appears to reduce the frequency of side effects without compromising antiviral prophylactic effectiveness)

» Renal function impairment{41} (since amantadine is not metabolized and is excreted primarily in the urine, toxic concentrations may accumulate in patients with impaired renal function; it may be necessary to reduce the dosage by 50% [£ 100 mg per day in such patients]; this appears to reduce the frequency of side effects without compromising antiviral prophylactic effectiveness)

Patient monitoringThe following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Seizure activity (patients with a history of epilepsy or other seizure disorders should be monitored for an increase in seizure activity {41})

Side/Adverse Effects

Note: In controlled studies, side effects, including nausea, dizziness, insomnia, nervousness, and impaired concentration, were reported in 5 to 10% of young healthy adults taking the standard adult dosage of 200 mg per day. {30} Side effects may diminish or cease after the first week of use. Serious, less frequent CNS side effects, such as confusion or seizures, have affected usually only elderly patients, and patients with renal disease, seizure disorders, or altered mental/behavioral conditions. Reducing the dosage by 50% (£ 100 mg per day) appears to reduce the frequency of side effects without compromising antiviral prophylactic effectiveness. {40}
A small number of suicide attempts, some of which have been fatal, have been reported in patients treated with amantadine. The incidence of suicide attempts is not known, and the pathophysiologic mechanism is not understood. Suicidal ideation as well as suicide attempts have been reported in patients with and without a prior history of psychiatric illness. Amantadine can exacerbate mental problems in patients with a history of psychiatric disorders or substance abuse. {41}{44}
Sporadic cases of possible neuroleptic malignant syndrome (NMS) have been reported in association with dose reduction or withdrawal of amantadine therapy. {41}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:Those indicating need for medical attentionIncidence less frequent {03}Anticholinergic-like effects (blurred vision; confusion; difficult urination; hallucinations)orthostatic hypotension (fainting)peripheral edema{41} (swelling of hands, feet, or lower legs)

Overdose
Overdose with amantadine has resulted in death. One gram is the lowest reported amount of amantadine resulting in lethal overdose.{49}

For specific information on the agents used in the management of amantadine overdose, see:
• Charcoal, Activated (Oral-Local) monograph; and/or
• Physostigmine (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:Symptoms of overdose{28}{29}{38}

Treatment of overdose
There is no specific antidote for the treatment of amantadine overdose.{49}

To decrease absorption:
Gastric decontamination with activated charcoal;{45}{48} gastric lavage may be performed if the ingestion was very recent.{49}

Vomiting should not be induced due to the risk of seizures after the overdose.{46}

To enhance elimination:
Because the excretion rate of amantadine increases rapidly when the urine is acidic, urinary acidifiers may be used to increase the elimination of amantadine from the body.{49}

Hemodialysis is not effective in removing significant amounts of amantadine from the body.{49}

Specific treatment:
Slow, intravenous administration of physostigmine may be used to treat central nervous system toxicity.{49} See the manufacturer's prescribing information or Physostigmine (Systemic) for specific guidelines for use of this product.

If necessary, appropriate antiarrhythmic, anticonvulsant, and antihypotensive therapy should be given.{41}{44}{49} However, care should be exercised when administering adrenergic agents such as isoproterenol because the dopaminergic activity of amantadine has been reported to induce malignant arrhythmias.{41} A sedative may be administered if hyperactivity should occur.{49}

Monitoring:
Blood electrolytes, blood pressure, pulse, respiration, temperature, urine pH, and urinary output should be monitored.{49} Electrocardiographic monitoring also may be required.{49} Patients should be observed for the possible development of arrhythmias, hyperactivity, hypotension, and seizures.{49}

Supportive care:
General supportive measures should be employed.{49} If there is no record of recent voiding, catherization should be done.{41}{44} Adequate hydration of the patient should be maintained;{47} if necessary, fluids should be given intravenously.{49}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Amantadine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):Before using this medication» Conditions affecting use, especially:Hypersensitivity to amantadine

Pregnancy—Amantadine crosses the placenta

Breast-feeding—Amantadine is distributed into breast milk

Use in the elderly—Geriatric patients may exhibit increased sensitivity to the anticholinergic-like side effects of amantadineOther medications, especially alcohol, anticholinergics or other medications with anticholinergic activity, other CNS stimulation–producing medications, quinidine, quinine, or trimethoprim and sulfamethoxazoleOther medical problems, especially congestive heart failure, peripheral edema, renal function impairment, seizure disorders, or a history of epilepsyProper use of this medication

» Proper storage

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

For use as an antiviral {03}
Receiving a flu shot if have not already done so

» Taking before exposure or as soon as possible after exposure

» Compliance with full course of therapy

» Importance of not missing doses and taking at evenly spaced times

Proper administration technique for oral liquid

For use as an antidyskinetic» Not taking more medication than the amount prescribed; not missing doses

May require up to 2 weeks for full benefitPrecautions while using this medication {03}» Avoiding alcoholic beverages

» Caution if mental acuity or eyesight is impaired

Caution when getting up suddenly from a lying or sitting position

» Checking with physician immediately if thoughts of suicide occur

Possible dryness of mouth, nose, and throat; using sugarless candy or gum, ice, or saliva substitute for relief of dry mouth; checking with physician or dentist if dry mouth continues for more than 2 weeks

General Dosing Information
In controlled studies, side effects, including nausea, dizziness, insomnia, nervousness, and impaired concentration, were reported in 5 to 10% of young healthy adults taking the standard adult dosage of 200 mg per day. Data suggest that comparable protection may be provided by a daily prophylactic dosage of 100 mg, but with fewer side effects. No studies have been done comparing 100-mg and 200-mg doses for the treatment of influenza A infection. {30}{34}

Amantadine does not prevent the potentially serious bacterial infections which may begin with influenza-like symptoms or which may co-exist with or occur as complications during the course of influenza.{49}

Patients receiving doses exceeding 200 mg per day should be observed closely for signs of increased incidence of side effects or toxicity. Monitoring of such patients for blood pressure, pulse, respiration, and temperature should be considered, especially for a few days following the increase in dose. Patients with active seizure disorders may be at increased risk for seizures while receiving amantadine. {30}

Changing from once-a-day to twice-a-day administration may eliminate or reduce the severity of side effects such as lightheadedness, insomnia, and nausea. {41}

If possible, plasma concentrations should be monitored in patients with end-stage renal disease since a single dose may provide adequate concentrations for as long as 7 to 10 days.

Some patients have attempted suicide by overdosing with amantadine; therefore, prescriptions should be written for the smallest quantity consistent with good patient management. {41}

Sporadic cases of possible neuroleptic malignant syndrome (NMS) have been reported in association with dose reduction or withdrawal of amantadine therapy. Therefore, patients should be observed carefully when the dosage of amantadine is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics. {41} The early diagnosis of NMS is important for the appropriate management of these patients.

For use in the prophylaxis and treatment of influenza type A virus infection {03}
Chemoprophylactic administration should be started in anticipation of contact with, or as soon as possible after exposure to, persons having influenza A virus infections. Administration should be continued for at least 10 days following exposure. In influenza epidemics, amantadine should be given daily during the epidemic (usually 6 to 8 weeks in most communities) or until active immunity can be expected from administration of inactivated influenza A virus vaccine. However, rimantadine, chemically similar to amantadine, has been reported to be ineffective when used prophylactically in household members while concurrently treating index cases for influenza A. This was apparently due to transmission of drug-resistant strains of the virus. {35}{36}

If administered concurrently with inactivated influenza A virus vaccine until protective antibodies develop, amantadine should be continued chemoprophylactically for 2 to 3 weeks after the vaccine has been administered. Amantadine may then be discontinued. However, since the vaccine is only 70 to 80% effective, more prolonged administration of amantadine may be beneficial in elderly or high-risk patients. If the vaccine is unavailable or contraindicated, amantadine should be administered for up to 90 days in cases of possible repeated or unknown exposure.

Treatment of the symptoms of influenza A virus infections should be started within 24 to 48 hours after their onset and should be continued for 48 hours after their disappearance. Cough may persist for several weeks.

For use in the treatment of parkinsonism {03}
Patients initially benefiting from the continuous administration of amantadine may experience a decline in effectiveness after a few months. Effectiveness may be restored by increasing the dose to 300 mg daily or temporarily discontinuing amantadine therapy for several weeks, and then resuming it. {41}

Patients who have concurrent serious illnesses or are receiving high doses of other antiparkinsonian medications may be started on 100 mg of amantadine once a day. After one to several weeks, the dose may be increased to 100 mg two times a day, if necessary. If response is still not optimal, patients may benefit from a further increase to 400 mg daily in divided doses. {41}

The maximal therapeutic benefit to be obtained with amantadine is usually seen within 1 week {44}.

Concurrent administration of anticholinergic antiparkinsonian medications or levodopa with amantadine may provide additional benefit, including reduction in fluctuations in improvement occurring with levodopa alone. If dosage reductions of levodopa are required because of side effects, the benefit lost by the reduction may be restored by the concurrent administration of amantadine.

If carbidopa and levodopa combination or levodopa is initially being administered concurrently with amantadine, the dose of amantadine should be maintained at 100 mg one or two times a day while the dose of carbidopa and levodopa combination, or levodopa is gradually increased to provide optimal benefit. {41}

Patients who have drug-induced extrapyramidal reactions may be started on 100 mg of amantadine two times a day. If response is not optimal, dose may be increased to 300 mg daily in divided doses. {41}

When amantadine is to be discontinued, dosage should be reduced gradually in order to prevent a sudden increase in parkinsonian symptoms. {41}For treatment of adverse effects
Neuroleptic malignant syndrome (NMS)—Recommended treatment consists of the following:
• Providing intensive symptomatic treatment and medical monitoring. {41}
• Treating any concomitant serious medical problems for which specific treatments are available; dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, have been used often in treating NMS; however, their effectiveness has not been demonstrated in controlled clinical trials. {41}

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.AMANTADINE HYDROCHLORIDE CAPSULES USPUsual adult and adolescent dose
Antiviral (systemic)
Oral, 200 mg once a day; or 100 mg every twelve hours. {03}{41}

Antidyskinetic
In patients who are taking amantadine alone: Oral, 100 mg two times a day. {41}{44}

In patients taking high doses of other antiparkinson medications or who have serious associated medical illnesses: Oral, 100 mg once a day. After one to several weeks, the dose may be increased to 100 mg two times a day, if necessary. {41}{44}

Note: If patients are not responding optimally at a dose of 200 mg daily, the dose may be increased up to 400 mg daily in divided doses. However, close physician supervision is necessary for these patients. {41}

Drug-induced extrapyramidal reactions
Oral, 100 mg two times a day. The dose may be increased to 300 mg daily in divided doses, if necessary. {41}{44}

[Antifatigue, multiple sclerosis–associated]1
Oral, 200 mg once a day; or 100 mg two times a day. {23}{24}{25}

Note: Adults with impaired renal function may require a reduction in dose as noted below. {03}{40} Elderly patients, and patients with seizure disorders or altered mental/behavioral conditions may require even further dose reductions {03}{40}.

Usual pediatric dose
Antiviral (systemic)
Neonates and infants up to 1 year of age: Safety and efficacy have not been established.

Children 1 to 9 years of age: Oral, 1.5 to 3 mg per kg of body weight every eight hours; or 2.2 to 4.4 mg per kg of body weight every twelve hours. Maximum daily dose should not exceed 150 mg. {03}{04}{12}

Note: For children 10 years of age or older weighing less than 45 kg of body weight, it may be advisable to use a dosage of 2.2 mg per kg of body weight every twelve hours. {30}
Some references recommend doses as low as 1.5 mg per kg of body weight every twelve hours in children 1 to 9 years of age.

Note: A daily dose of amantadine exceeding 100 mg should be used with caution in persons 65 years of age or older for influenza prophylaxis or treatment. If the patient has any renal function impairment, the dose should be reduced further. {30}